The focus of this proposal is to dissect the role of Protein Homeostasis in enterovirus replication, evolution and pathogenesis. The paradigm for these studies is that enteroviruses are highly dependent on the cellular chaperone and quality control (QC) machinery for their protein production and function. Furthermore, given the very high mutation rates of these viruses, we hypothesize that the chaperones and QC network is key to modulating virus diversity, evolution and pathogenesis. We propose to examine how host protein homeostasis machinery participates in enterovirus replication and modulates viral diversity and how viruses use this machinery to alleviate the detrimental effect of mutations that accumulate during replication. We have recently demonstrated that high mutation rate of enteroviruses is essential for their adaptability and pathogenesis. Thus, restricting viral diversity through the modulation of protein homeostasis machinery could provide powerful ways to attenuate virus pathogenesis. This proposal combines computational, cell biological, molecular and systems approaches to define the host protein homeostasis network involved in enteroviral replication and determine the role of this network to viral evolution, diversity, and pathogenesis. These new approaches are essential given the failure of traditional strategies to achieve any therapeutic intervention against enteroviruses (such as polio, coxsackie, and enterovirus 71) and it has the potential to set the basis for the prevention of current and emerging enteroviral diseases . This proposal describes a multidisciplinary and highly integrated approach that is designed to obtain this critically important information. We propose 3 Specific Projects and 2 Cores: Project 1: Host-enterovirus circuitry revealed by global analysis of cellular networks; Project 2: Role of cellular factors in enterovirus protein homeostasis and function; and Project 3: Role of protein homeostasis in enterovirus population diversity, evolution and pathogenesis. Core A: Administrative Core; and Core B: High-throughput functional genomics and proteomics core.